The proposal describes the initial development of a fundamentally new type of optical biosensor that utilizes active generation of light output with a plastic-based laser surface structure to provide high resolution label-free sensing of biomolecular interactions. While the laser biosensor can be produced inexpensively over large surface areas by a replica molding process, the detection instrument that we propose building will be compact, inexpensive, and capable of resolution sufficient for direct detection of small molecule binding to immobilized protein targets with high signal-to-noise ratio. The first funded effort, proposed here, would enable development of the sensor fabrication process, construction of a detection instrument, and performance of a set of initial feasibility studies for small molecule direct binding assays. Our long-term goal is to develop this biosensor method into a general-purpose detection platform for small molecule screening, cell-based assays, biomarker diagnostics, and environmental detection by taking advantage of its potential for imaging detection and single protein molecule detection resolution. PUBLIC HEALTH RELEVANCE: The proposed project is aimed at the development of a high resolution biomolecular interaction detection technology that can be utilized to address the large swath of the proteome consisting of proteins that have no enzymatic function and are hence not "screenable" using conventional technologies. Proteins that modulate transcription, those that receive signals from the cellular surface, and those that are involved in DNA damage repair are among the thousands of proteins that do not have enzymatic activity but whose modulation with drugs could lead to treatments for a host of diseases. The stagnation in the number of new protein targets underscores the need for new technologies for high-throughput screening: in the years from 1989-2000, only 6% of the new molecular entities hit previously undrugged targets. Thus, to get at new targets and identify new compounds that are true breakthroughs in disease treatment, we need detection methodologies that can be utilized to rapidly identify small molecule binders for proteins, not merely enzymatic inhibitors.